Dibenzothiophenes

ABSTRACT

Dibenzothiophenes of the formula ##STR1## wherein R, R 1  and R 2  are as hereinafter described, prepared, inter alia, from the correspondingly substituted thiophenol and haloketocyclohexane are described. The dibenzothiophenes of the invention are useful antiinflammatory, analgesic and antirheumatic agents.

This is a continuation of application Ser. No. 68,297, now abandoned,filed Aug. 20, 1979, which in turn is a continuation of Ser. No.861,747, filed Dec. 19, 1977, now abandoned, which is a division of Ser.No. 669,940, filed Mar. 24, 1976, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to compounds of the formula ##STR2## wherein R ishydrogen, halogen, hydroxy, cyano, lower alkyl, hydroxy-lower alkyl,lower alkoxy, acyl, benzyloxy, lower alkylthio, trifluoromethyl, nitro,amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-loweralkylsulfamoyl or difluoromethylsulfonyl; R₁ is halogen, cyano, loweralkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acylamido, benzyloxy,lower alkylthio, trifluoromethyl, hydroxy, nitro, amino, mono-loweralkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl ordifluoromethylsulfonyl, or R taken together with an adjacent R₁ is alsolower alkylenedioxy; R₂ is ##STR3## wherein A is hydroxy, lower alkoxy,amino-lower alkoxy, mono-lower alkylamino-lower alkoxy ordi-loweralkylamino-lower alkoxy, X and Y, independently, are hydrogen orlower alkyl, and m is 1 to 7, or R₂ is ##STR4## wherein B is hydroxy,carboxy, lower alkoxy, amino, hydroxyamino, mono-lower alkylamino,di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-loweralkoxy or di-lower alkylamino-lower alkoxy, Y and X, independently, arehydrogen or lower alkyl; and n is 1 to 7; when X and Y are different,their enantiomers; when B is hydroxy or carboxy, salts thereof withpharmaceutically acceptable bases; and when R or R₁ is amino, mono-loweralkylamino or di-lower alkylamino, and/or when B or A is amino-loweralkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-loweralkoxy, addition salts thereof with pharmaceutically acceptable acids.The dibenzothiophenes of formula I are useful as antiinflammatory,analgesic and antirheumatic agents.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" denotes a straight or branchedchain hydrocarbon group containing 1-7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,neopentyl, pentyl, heptyl and the like. The term "lower alkoxy" denotesan alkyl ether group in which the alkyl group is as described above, forexample, methoxy, ethoxy, propoxy, isopropxy, butoxy, pentoxy and thelike. The term "lower alkylthio" denotes an alkyl thioether group inwhich the alkyl group is as described above, for example, methylthio,ethylthio, propylthio, isopropylthio, butylthio, pentylthio and thelike. The term "halogen" denotes all the halogens, that is, bromine,chlorine, fluorine and iodine; bromine and chlorine are preferred. Theterm "acyl" denotes an "alkanoyl" group derived from an aliphaticcarboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl,propionyl, and the like, and an "aroyl" group derived from an aromaticcarboxylic acid, such as benzoyl and the like. The term "lower alkylene"denotes a straight or branched chain alkylene of 1-7 carbon atoms, forexample, methylene, ethylene, propylene, butylene, methylmethylene andthe like. The term "lower alkylenedioxy" preferably denotesmethylenedioxy and the like.

Exemplary of mono-lower alkylamino are methylamino, ethylamino and thelike. Exemplary of di-lower alkylamino are dimethylamino, diethylaminoand the like. Exemplary of amino-lower alkoxy are aminomethoxy,aminoethoxy and the like. Exemplary of mono-lower alkylamino-loweralkoxy are methylamino-methoxy ethylaminoethoxy and the like. Exemplaryof di-lower alkylamino-lower alkoxy are dimethylaminomethoxy,diethylaminoethoxy and the like. Exemplary of di-lower alkylsulfamoylare dimethylsulfamoyl, diethylsulfamoyl and the like.

The invention relates to compounds of the formula ##STR5## wherein R ishydrogen, halogen, hydroxy, cyano, lower alkoxy, hydroxy-lower alkyl,lower alkoxy, acyl, benzyloxy, lower alkylthio, trifluoromethyl, nitro,amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-loweralkylsulfamoyl or difluoromethylsulfonyl; R₁ is halogen, cyano, loweralkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acylamido, benzyloxy,lower alkylthio, trifluoromethyl, hydroxy, nitro, amino, mono-loweralkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl ordifluoromethylsulfonyl, or R taken together with an adjacent R₁ is alsolower alkylenedioxy; R₂ is ##STR6## wherein A is hydroxy, lower alkoxy,amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-loweralkylamino-lower alkoxy, Y and X, independently, are hydrogen or loweralkyl, and m is 1 to 7, or R₂ is ##STR7## wherein B is hydroxy, carboxy,lower alkoxy, amino, hydroxyamino, mono-lower alkylamino, di-loweralkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy ordi-lower alkylamino-lower alkoxy; Y and X, independently, are hydrogenor lower alkyl; and n is 1 to 7, and

when X and Y are different, their enantiomers; when B is hydroxy orcarboxy, salts thereof with pharmaceutically acceptable bases; and whenR or R₁ is amino, mono-lower alkylamino or di-lower alkylamino, and/orwhen B or A is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy ordi-lower alkylamino-lower alkoxy, addition salts thereof withpharmaceutically acceptable acids.

Preferred dibenzothiophenes of the invention are those characterized bythe formulas ##STR8## wherein R'₁ is halogen, lower alkyl or loweralkoxy, preferably R'₁ is halogen or lower alkyl, and most preferablyR'₁ is halogen, and X and Y are as previously described, theirenantiomers when X and Y are different, and salts of the compounds offormula I' with pharmaceutically acceptable bases. Preferably, informula I, m is 2 and n is 1.

Preferred compounds of formula I are:

racemic 8-chloro-α-methyl-dibenzothiophene-3-acetic acid;

(+) 8-chloro-α-methyl-dibenzothiophene-3-acetic acid;

(-) 8-chloro-α-methyl-dibenzothiophene-3-acetic acid;

racemic 2-(8-chloro-3-dibenzothienyl)propanol;

2-(8-chloro-3-dibenzothienyl)ethanol;

8-chloro-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-acetamide.

Exemplary of compounds of this invention corresponding to formula I are:

8-chloro-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-acetic acid ethyl ester;

8-methoxy-dibenzothiophene-3-acetic acid;

8-nitro-dibenzothiophene-3-acetic acid;

7-methoxy-dibenzothiophene-3-acetic acid;

7-chloro-dibenzothiophene-3-acetic acid;

8-methyl-dibenzothiophene-3-acetic acid;

6-chloro-dibenzothiophene-3-acetic acid;

8,9-dichloro-dibenzothiophene-3-acetic acid;

α-methyl-dibenzothiophene-3-acetic acid;

7-methyl-dibenzothiophene-3-acetic acid;

7,8-dichloro-dibenzothiophene-3-acetic acid;

8-chloro-9-methyl-dibenzothiophene-3-acetic acid;

8-difluoromethylsulfonyl-dibenzothiophene-3-acetic acid;

racemic 2-(8-chloro-3-dibenzothienyl)propanol methyl ether;

8-chloro-7-methyl-dibenzothiophene-3-acetic acid;

8-sulfamoyl-dibenzothiophene-3-acetic acid;

8-benzoyl-dibenzothiophene-3-acetic acid;

8-fluoro-dibenzothiophene-3-acetic acid;

8-trifluoromethyl-dibenzothiophene-3-acetic acid;

6,7-dichloro-dibenzothiophene-3-acetic acid;

9-chloro-8-sulfamoyl-dibenzothiophene-3-acetic acid;

8-methylthio-dibenzothiophene-3-acetic acid;

8-ethyl-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-acetic acid dimethylaminoethyl ester;

8-methyl-dibenzothiophene-3-acetic acid ethyl ester;

8-dimethylsulfamoyl-dibenzothiophene-3-acetic acid;

8-iodo-dibenzothiophene-3-acetic acid;

8-chloro-N,N-dimethyl-dibenzothiophene-3-acetamide;

8-cyano-dibenzothiophene-3-acetic acid;

8-acetyl-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-acetic acid dimethylaminoethyl esterhydrochloride;

8-benzyloxy-dibenzothiophene-3-acetic acid;

7,8-methylenedioxy-dibenzothiophene-3-acetic acid;

8-hydroxy-dibenzothiophene-3-acetic acid;

7-chloro-dibenzothiophene-3-acetic acid ethyl ester;

9-chloro-dibenzothiophene-3-acetic acid ethyl ester;

8-bromo-dibenzothiophene-3-acetic acid ethyl ester;

8-acetamido-dibenzothiophene-3-acetic acid ethyl ester;

8-chloro-dibenzothiophene-3-propionic acid ethyl ester;

8-chloro-α,α-dimethyl-dibenzothiophene-3-acetic acid ethyl ester;

8-chloro-α-methyl-dibenzothiophene-3-acetic acid dimethylaminoethylester;

8-chloro-α-methyl-dibenzothiophene-3-acetamide;

8-trifluoromethyl-dibenzothiophene-3-acetic acid ethyl ester;

6,7-dichloro-dibenzothiophene-3-acetic acid ethyl ester;

8,9-dichloro-dibenzothiophene-3-acetic acid ethyl ester;

8-methylthio-dibenzothiophene-3-acetic acid ethyl ester;

8-fluoro-dibenzothiophene-3-acetic acid ethyl ester;

α-methyl-dibenzothiophene-3-acetic acid ethyl ester;

8-N,N-dimethylsulfamoyl-dibenzothiophene-3-acetic acid ethyl ester;

7,8-dichloro-dibenzothiophene-3-acetic acid ethyl ester;

8-nitro-dibenzothiophene-3-acetic acid ethyl ester;

7-dimethylaminodibenzothiophene-3-acetic acid ethyl ester; and the like.

The compounds of formula I can be prepared by alkylating a compound ofthe formula ##STR9## wherein R and R₁ are as previously described, withthe corresponding haloketocycloalkene compound of the formula ##STR10##wherein HAL and R₂ are as previously described, to yield a compound ofthe formula ##STR11## wherein R, R₁ and R₂ are as previously described.The reaction is conveniently carried out in a non-polar solvent, forexample, a hydrocarbon, such as benzene, toluene and the like, or apolar solvent, such as dimethylsulfoxide, dimethylformamide,hexamethylphosphoric triamide, an alkanol such as ethanol, and the like.The reaction temperature is not critical. Preferably, the reaction iscarried out at a temperature in the range of from about room temperatureto about the reflux temperature of the reaction mixture. The molar ratioof the reactants is not critical. Preferably, they are reacted at a 1:1molar ratio.

A compound of formula IV is converted to a compound of the formula##STR12## wherein R, R₁ and R₂ are as previously described, by thermalcyclization or by utilizing a cyclizing agent, such as polyphosphoricacid, and the like. Preferably, the reaction is carried out at atemperature in the range of from about -20° to about 120°. The reactioncan be conveniently carried out with or without a solvent. Exemplary ofconvenient solvents are acetic acid and the like.

An ester of formula I can be converted to the corresponding acid, i.e.,the compounds of formula I wherein B is hydroxy, by saponificationaccording to known procedures, for example, by reaction with an alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide and thelike, and subsequent treatment with a mineral acid, for example, ahydrohalic acid such as hydrochloric acid or the like. Additionally, anester of formula I can be converted to the corresponding acid bytreatment with a mineral acid, for example, a hydrohalic acid such ashydrochloric acid or the like, in the presence of an organic solventsuch as acetic acid, preferably at the reflux temperature of thereaction mixture.

The separation of the desired compound of formula I and itscorresponding acid from the reaction mixture can be effected utilizingknown techniques such as, for example, filtration, crystallization,distillation and the like.

Furthermore, a salt of an acid of formula I, i.e., a salt of compoundsof formula I wherein B is hydroxy, can be converted to a compound offormula I wherein B is amino-lower alkyl, mono-lower alkylamino-loweralkyl or di-lower alkylamino-lower alkyl by known procedures. Forexample, a salt of an acid of formula I is reacted with an amino-loweralkyl halide, mono-lower alkylamino-lower alkyl halide or di-loweralkylamino-lower alkyl halide, exemplary of which are aminoethylchloride, methylamino-ethyl bromide, diethylaminomethyl chloride and thelike, to yield the desired end product. The temperature at which thereaction is effected is not critical; conveniently, the reaction iscarried out at a temperature in the range of from about room temperatureto about the reflux temperature of the reaction mixture. Conveniently,the reaction can be carried out in a polar solvent, such asdimethylformamide, dimethylsulfoxide or the like. The molar ratio ofreactants is not critical. Preferably, the reactants are utilized in a1:1 molar ratio.

The starting materials of formula II are known compounds or can beprepared in an analogous manner to known compounds. Exemplary of suchcompounds are:

4-chlorothiophenol;

5-chlorothiophenol; and

4-nitrothiophenol.

The starting materials of formula III can be prepared by halogenating acompound of the formula ##STR13## wherein R₂ is as previously described;to yield a compound of the formula ##STR14## wherein HAL and R₂ are aspreviously described.

The compounds of formula VI are known compounds or can be prepared in ananalogous manner to known compounds.

The halogenation is effected utilizing known procedures, for example,utilizing a halogen such as bromine in ether, at a temperature of -10°C. Exemplary of such compounds are:

3-bromo-4-ketocyclohexaneacetic acid;

3-bromo-4-ketocyclohexaneacetic acid ethyl ester; and the like.

Exemplary of the intermediates of formula IV are:

3-(4-chloro-phenylthio)-4-oxocyclohexaneacetic acid and ethyl esterthereof;

3-(4-bromo-phenylthio)-4-oxocyclohexaneacetic acid and methyl esterthereof; and the like.

The 1,2,3,4-tetrahydrodibenzothiophenes of formula V are then aromatizedto the corresponding compound of formula I.

A compound of formula V is converted to a compound of formula Iutilizing a dehydrogenating agent, for example, p-chloranil,o-chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), sulfur,palladium on carbon, lead oxide, and the like, in the presence of asolvent, for example, xylene, benzene, toluene, quinoline,dimethylsulfoxide (DMSO), dioxane, dimethylformamide (DMF). Thearomatization is carried out at a temperature in the range of from aboutroom temperature to about the reflux temperature of the reactionmixture; preferably, it is carried out at the reflux temperature of thereaction mixture. The compound of formula I can be separated from thereaction mixture by known procedures, included among which are, forexample, filtration, crystallization, distillation, and the like.7-Nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide is made bynitration of dibenzothiophene-3-carboxylic acid ethyl ester 5-oxidewhich in turn is made by oxidation of dibenzothiophene-3-carboxylic acidethyl ester with chlorine.

An acid of formula I, wherein B is hydroxy, can be converted to thecorresponding ester by known procedures. For instance, (a) an acid offormula I can be reacted with an alkanol such as methanol, ethanol,propanol or the like, in the presence of an acid catalyst; at atemperature in the range of from about room temperature to the refluxtemperature of the reaction mixture, or (b) an alkali metal salt of anacid of formula I, such as the sodium salt, can be reacted with asubstituted or unsubstituted alkyl halide utilizing known reactionconditions, for example, in an inert solvent such as benzene, toluene,dimethylformamide or the like, at a temperature in the range of fromabout room temperature to the reflux temperature of the reactionmixture.

A compound of formula I, wherein R or R₁ is amino, can be converted tothe corresponding compound wherein R or R₁ is dialkylamino, utilizingknown procedures, for example, utilizing hydrogen at a pressure of fromabout 1 atmosphere to about several atmospheres and a catalyst such asRaney nickel, together with an alkyl aldehyde such as formaldehyde, at atemperature in the range of from about room temperature to about 100°,in a solvent, for example, an alkanol such as methanol, ethanol or thelike. The alkylation can also be carried out by treating the amine, forexample, with trimethylphosphate under known conditions.

A compound of formula I, wherein R, R₁ or A is alkoxy, can be convertedto the corresponding compound, wherein R, R₁ or A is hydroxy, by knownprocedures. For example, a compound of formula I bearing an alkoxy groupcan be treated with a mineral acid, for example, a hydrohalic acid suchas hydrobromic acid, or the like, in a solvent, for example, alkanolssuch as ethanol, propanol, or the like, at a temperature in the range offrom about room temperature to about the reflux temperature of thereaction mixture. The conversion can also be effected utilizing a Lewisacid, such as aluminum tribromide, aluminum trichloride, boron bromide,tin tetrachloride or the like, in a solvent such as benzene, toluene,dimethylformamide or the like.

An alcohol of formula I, i.e., an alcohol prepared from thecorresponding ketone of formula III, wherein A is hydroxy, can beconverted to the corresponding compound of formula I wherein A is loweralkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy ordi-lower alkylamino-lower alkoxy by known procedures. For example, analcohol of formula I, wherein A is hydroxy, is treated with an alkalimetal such as sodium. The resulting compound is then treated with ahalide (X) of the formula RX, wherein R is lower alkyl, amino-loweralkyl, mono-lower alkylamino-lower alkyl or di-lower alkylamino-loweralkyl, utilizing known reaction conditions.

A compound of formula I, wherein B is lower alkoxy, can be de-esterifiedto the corresponding compound of formula I wherein B is hydroxy, with analkali hydroxide, such as sodium hydroxide, potassium hydroxide or thelike, in the presence of a solvent, for example, an alkanol such asmethanol, ethanol or the like. The de-esterification can be carried outat a temperature in the range of from about room temperature to aboutthe reflux temperature of the reaction mixture, preferably, it iscarried out at the reflux temperature of the reaction mixture. Thecompound of formula I can be separated from the reaction mixture byknown procedures. The de-esterification can also be carried oututilizing an acid such as hydrochloric acid under known conditions.

An ester of formula I can be converted to the corresponding alcohol,e.g., wherein A is hydroxy, by known procedures. For example, an esterof formula I can be treated with a reagent such as lithium aluminumhydride, at a temperature in the range of from about room temperature tothe reflux temperature of the reaction mixture. Thereafter, thecorresponding alcohol which is formed can be separated by knownprocedures.

A compound of formula I, wherein n is 1, X and Y are hydrogen and B islower alkoxy, e.g., dibenzothiophene-3-acetic acid ethyl ester,8-methyldibenzothiphene-3-acetic acid ethyl ester and7-dimethylamiodibenzothiophene-3-acetic acid ethyl ester can besynthetized from the corresponding carboxylic acids, for example,dibenzothiophene-3-carboxylic acid,8-methyldibenzothiophene-3-carboxylic acid and7-dimethylaminodibenzothiophene-3-carboxylic acid via the Arndt-Eistertreaction which involves conversion of the carboxylic acids to the acidchlorides followed by reaction with diazomethane to yield thediazoketones. Rearrangement in alcohol solution in the presence ofsilver ion yielded the corresponding acetic acid ethyl esters.

A compound of formula I, wherein R₁ is acylamido, can be converted tothe corresponding compound of formula I, wherein R₁ is amino, bytreatment with an inorganic acid, for example, a hydrohalic acid such ashydrochloric acid or the like, utilizing known reaction conditions.

Alkylation of 8-chlorodibenzothiophene-3-acetic acid ethyl ester in thealpha-position can be carried out by dissolving the ester in liquidammonia containing sodium amide and then adding methyl iodide or butylbromide to produce either 8-chloro-alpha-methyldibenzothiophene-3-aceticacid ethyl ester or 8-chloro-alpha-butyldibenzothiophene-3-acetic acidethyl ester. Realkylating 8-chloro-alpha-methyldibenzothiophene-3-aceticacid ethyl ester with methyl iodide as above yields the8-chloro-alpha,alpha-dimethyldibenzothiophene-3-acetic acid ethyl ester.Hydrolysis of the ester yields the corresponding acids.

The acids of formula I, i.e., the compounds of formula I, wherein B ishydroxy, and salts of such acids with bases, can be converted to acompound of formula I wherein B is amino-lower alkoxy, mono-loweralkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy by knownprocedures. For example, a salt of an acid of formula I is reacted withan amino-lower alkyl halide, mono-lower alkylamino-lower alkyl halide ordi-lower alkylamino-lower alkyl halide, exemplary of which areaminomethyl chloride, methylamino-ethyl bromide, diethylaminomethylchloride and the like, to yield the desired end product. The temperatureat which the reaction is effected is not critical; conveniently, thereaction is carried out at a temperature in the range of from about roomtemperature and about the reflux temperature of the reaction mixture.Conveniently, the reaction can be carried out in a polar solvent, suchas dimethylformamide, dimethylsulfoxide or the like. The molar ratio ofreactants is not critical. Preferably, the reactants are utilized in a1:1 molar ratio.

The compounds of formula I when R or R₁ is amino, mono-lower alkylamino,di-lower alkylamino, and/or when B or A is amino-lower alkoxy,mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy,from addition salts with pharmaceutically acceptable organic orinorganic acids such as hydrohalides, e.g., hydrochloride, hydrobromide,hydroiodide, other mineral acid salts such as sulfate, nitrate,phosphate and the like, alkyl- and mono-arylsulfonates such asethanesulfonate, toluenesulfonate, benzenesulfonate, or the like, otherorganic acid salts such as acetate, tartrate, maleate, citrate,benzoate, salicylate, ascorbate and the like.

The compounds of formula I, when B is hydroxy or carboxy, form saltswith pharmaceutically acceptable bases. Exemplary of such bases arealkali metal hydroxides, such as sodium hydroxide, potassium hydroxide,and the like; alkaline earth hydroxides, such as calcium hydroxide,barium hydroxide and the like; sodium alkoxides, such as sodiumethanolate, potassium ethanolate and the like; organic bases such aspiperidine, diethanolamine, N-methylglucamine, and the like. Alsoincluded are the aluminum salts of the compounds of formula I, as above.

The compounds of formula I, including the salts of those compounds offormula I which form salts with pharmaceutically acceptable bases andacids, possess anti-inflammatory, analgesic and anti-rheumatic activity,and are therefore useful as anti-inflammatory, analgesic andanti-rheumatic agents. The compounds of formula I also exhibit asignificantly low incidence of ulcerogenic activity, which renders themhighly desirable as anti-inflammatory, analgesic and anti-rheumaticagents. Their pharmacologically useful activities are demonstrated inwarm-blooded animals using standard procedures.

For example, the anti-inflammatory activity is demonstrated in Albinorats of Hart Strain, weighing 125-155 gms. The test animals are given 10mls. of vehicle¹, which contains the test compound per kg. of bodyweight. The animals are treated daily for 5 consecutive days. Threehours after the first treatment, 0.05 ml. of an 0.5% suspension of heatkilled dessiccated Mycobacterium butyricum in U.S.P. olive oil, whichhas been sterilized for 30 minutes, is injected into the right hind footof each rat. The paw volume is measured immediately after the injectionof the adjuvant and again 96 hours later. The difference is recorded asvolume of edema. The paw volume is measured by immersion of the paw intoa column of mercury to an ink mark exactly at the level of the lateralmalleolus. Percent inhibition is calculated by dividing the averagecontrol edema minus the average treatment edema by the average controledema times 100. The percent inhibition is plotted against dose onsemi-logarithmic probability paper and the dose required to produce a30% reduction in edema is estimated therefrom and is expressed as ED₃₀.

When 8-chloro-dibenzothiophene-3-acetic acid, which has demonstrated anLD₅₀ of, for example, 775 mg. p.o. in mice, is utilized as the testsubstance at a dosage of 0.03 gm. p.o., an anti-inflammatory activity isobserved (ED₃₀ =1.8 mg/kg/day).

The analgesic activity of the compounds of the invention isdemonstrated, for example, employing the method which is a modificationof that described by Eddy (1950), Wolfe and MacDonald (1944) and Eddyand Leimbach (1952). The method determines the reaction time of micedropped onto a hot plate maintained at 55°±0.5° C. Six groups of malemice (5 mice/group) weighing between 20-30 grams are utilized. Theinitial reaction time of these mice is determined once, and the reactiontime of each group is then averaged. The mice are then administered thevehicle and/or the compound to be tested by the oral, intraperitoneal orsubcutaneous route. The average reaction time of each group isdetermined again at 30, 60 and 90 minutes after compound administrationand is compared to controls. Reaction time is recorded as percentchanges from control. All groups are averaged before and aftertreatment. A combined reaction time average (recorded as percent changeof reaction time threshhold from controls) for all three periods isplotted against dose on graph paper, and a curve is drawn. The ED.sub.50 is read from this curve.

When 8-chloro-dibenzothiophene-3-acetic acid, which has demonstrated anLD₅₀ of, for example, 775 mg. p.o. in mice, is utilized as the testsubstance, analgesic activity is observed at an ED₅₀ of 120 mg/kg afteroral administration.

The compounds of formula I, their enantiomers and salts thereof asherein described, have effects qualitatively similar to those ofphenylbutazone and indomethacin, known for their therapeutic uses andproperties. Thus, the end products of this invention demonstrate apattern of activity associated with antiinflammatory agents of knownefficacy and safety.

The compounds of formula I, their enantiomers and salts thereof asherein described, can be incorporated into standard pharmaceuticaldosage forms, for example, they are useful for oral or parenteralapplication with the usual pharmaceutical adjuvant material, forexample, organic or inorganic inert carrier materials such as water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, polyalkylene-glycols, and the like. The pharmaceuticalpreparations can be employed in a solid form, for example, as tablets,troches, suppositories, capsules, or in liquid form, for example, assolutions, suspensions, or emulsions. Pharmaceutical adjuvant materialscan be added and include preservatives, stabilizers, wetting oremulsifying agents, salts to change the osmotic pressure or to act asbuffers. The pharmaceutical preparations can also contain othertherapeutically active substances.

Since the compounds of the invention when X and Y in formula I aredifferent possess an asymmetric carbon atom, they are ordinarilyobtained as racemic mixtures. The resolution of such racemates into theoptically active isomers can be carried out by known procedures. Someracemic mixtures can be precipitated as eutectics and can thereafter beseparated. Chemical resolution is, however, preferred. By this method,diastereomers are formed from the racemic mixture with an opticallyactive resolving agent, for example, an optically active base, such asd-α-methylbenzylamine, which can be reacted with the carboxyl group. Theformed diastereomers are separated by selective crystallization andconverted to the corresponding optical isomer. Thus, the inventioncovers the racemates of the compounds of formula I as well as theiroptically active isomers.

The following Examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise stated.

EXAMPLE 1 Preparation of 8-chloro-α-methyldibenzothiophene-3-acetic acid

To a 500 ml. three-necked flask containing 100 ml. of liquid ammonia and0.009 mol of sodium amide (prepared from 0.2 g. sodium) was addeddropwise a solution of 2.6 g. of 8-chlorodibenzothiophene-3-acetic acidethyl ester in 20 ml. of ether and 10 ml. of tetrahydrofuran. Thesolution was stirred for 1 hour and then a solution of 1.3 g. of methyliodide in 20 ml. of ether was added dropwise. After the solution wasstirred for 1 hour, 0.5 g. of ammonium chloride was added and theammonia allowed to evaporate. Then the residue was acidified with dilutehydrochloric acid and the oil extracted with ether. The ether wasremoved and the residue slowly solidified. The solid was crystallizedfrom pentane and yielded 1.5 g. of8-chloro-α-methyldibenzothiophene-3-acetic acid ethyl ester, m.p.73°-75°.

1.3 G. of 8-chloro-α-methyldibenzothiophene-3-acetic acid ethyl esterwas added to 100 ml. of absolute ethanol containing 0.6 g. of potassiumhydroxide. The solution was refluxed for 3 hours. Then the solvent wasremoved in vacuo and the residue dissolved in 30 ml. of water. Thesolution was acidified with dilute hydrochloric acid and the oilextracted with ether. The ether was removed and the residue,crystallized from ethyl acetate, yielded 0.9 g. of8-chloro-α-methyldibenzothiophene-3-acetic acid, m.p. 190°-192°.

EXAMPLE 2 Preparation of 8-chloro-α,α-dimethyldibenzothiophene-3-aceticacid

To a 500 ml. three-necked flask containing 400 ml. of liquid ammonia and0.017 mol of sodium amide (prepared from 0.39 g. of sodium) was addeddropwise a solution of 5.1 g. of8-chloro-α-methyldibenzothiophene-3-acetic acid ethyl ester in 40 ml. oftetrahydrofuran. The solution was stirred for 1 hour and then a solutionof 2.3 g. of methyl iodide in 50 ml. of ether was added dropwise. Afterthe addition, the solution was stirred for 3 hours. Then 1.1 g. ofammonium chloride was added and the ammonia allowed to evaporate. Theresidue was acidified with dilute hydrochloric acid and the oilextracted with ether. The ether was removed and the residue,crystallized from pentane, yielded 1.8 g. of8-chloro-α,α-dimethyldibenzothiophene-3-acetic acid ethyl ester, m.p.57°-61°.

1.8 G. of 8-chloro-α,α-dimethyldibenzothiophene-3-acetic acid ethylester was added to a solution of 0.4 g. of potassium hydroxide in 100ml. of ethanol. After the solution had refluxed for 3 hours, the solventwas removed in vacuo. The residue was dissolved in 75 ml. of water andthe solution acidified with dilute hydrochloric acid. The crude acid wasextracted with ethyl acetate. The solvent was removed in vacuo and theresidue, crystallized from acetonitrile, yielded 0.58 g. of8-chloro-α,α-dimethyldibenzothiophene-3-acetic acid, m.p. 198°-200°.

EXAMPLE 3 Preparation of 8-chloro-α-butyldibenzothiophene-3-acetic acid

To a 500 ml. three-necked flask containing 200 ml. of liquid ammonia and0.014 mol of sodium amide (prepared from 0.32 g. of sodium) was addeddropwise a solution of 3.8 g. of 8-chlorodibenzothiophene-3-acetic acidethyl ester in 40 ml. of tetrahydrofuran. The solution was stirred for 1hour and a solution of 1.8 g. of butyl bromide in 50 ml. of ether wasadded dropwise. The solution was stirred for 1 hour, 0.9 g. of ammoniumchloride added and the ammonia allowed to evaporate. The residue wasacidified with dilute hydrochloric acid and the oil extracted withether. The ether was removed by distillation and the residue remaining(3.9 g.) was crude 8-chloro-α-butyldibenzothiophene-3-acetic acid ethylester.

To a solution of 0.9 g. of potassium hydroxide in 100 ml. of alcohol wasadded 3.9 g. of crude 8-chloro-α-butyldibenzothiophene-3-acetic acidethyl ester. The solution was refluxed for 3 hours and then the solventwas removed in vacuo. Water was added to the residue and the insolubleby-products extracted with ether and the ether discarded. The clearaqueous solution was acidified with dilute hydrochloric acid and thedesired product extracted with ethyl acetate. The solvent was removed invacuo and the residue, after crystallization from acetonitrile, yielded1 g. of 8-chloro-α-butyldibenzothiophene-3-acetic acid, m.p. 156°-159°.

EXAMPLE 4 Preparation of 3-bromo-4-oxocyclohexaneacetic acid ethyl ester

74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. ofanhydrous ether were placed in a 3 l. three-necked flask, provided witha thermometer, nitrogen inlet, dropping funnel, condenser and stirrer.The solution was cooled to -10° by means of a dry ice-acetone bath, and64.0 g. of bromine was added dropwise over a period of 30-40 minutes.The resulting colorless solution was washed three times with 100 ml. ofwater, then two times with 125 ml. of cold saturated sodium bicarbonatesolution followed by 100 ml. of water. The combined aqueous solutionswere extracted twice with 150 ml. of ether. The combined ether extractswere dried over anhydrous magnesium sulfate, and the ether was removedby distillation from a steam bath at atmospheric pressure to give aresidue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester,weighing 105 g.

EXAMPLE 5 Preparation of 3-(4-chlorophenylthio)-4-oxocyclohexaneaceticacid ethyl ester

58 G. of 4-chlorothiophenol and a solution of 26.5 g. of 85% potassiumhydroxide in 1500 ml. of ethanol were each placed in a 3 l. three-neckedflask, provided with a condenser, nitrogen inlet, dropping funnel andstirrer. The solution was brought to reflux and a solution of 105 g. ofcrude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 500 ml. ofethanol was added over a period of one hour to the refluxing solution.After the addition, the solution was stirred at reflux for one hour,cooled to room temperature, and filtered to remove the potassiumbromide. After removal of the ethanol in vacuo (steam bath, rotaryevaporator), 300 ml. of water was added to the residue, the product wasextracted three times with 200 ml. of ether and the ether extract driedover anhydrous magnesium sulfate. After removal of ether from a steambath at atmospheric pressure, the residue, weighing 128 g., wasdistilled in vacuo. A forerun weighing 28.7 g. was collected at100°-190° (1 mm.), while 76.4 g. of a main fraction collected at190°-222° (1 mm.). A gas chromatographic determination of the mainfraction showed that 3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acidethyl ester was present.

EXAMPLE 6 Preparation of8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester

76.4 G. of the above-distilled3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester (bp190°-222°/1 mm.) was added to 1000 g. of polyphosphoric acid, containedin a 2 l. three-necked flask, provided with a stirrer and condenser. Themixture was heated on a steam bath for 90 minutes and then poured into amixture of 1 kilogram of ice and 1 liter of water. The mixture wasstirred until the dark oily complex was decomposed and a light yellowcolor appeared. The product was extracted twice with 500 ml. of ether.The ether extract was washed twice with 100 ml. of water, then with 100ml. of saturated sodium bicarbonate solution, dried over anhydrouspotassium carbonate, and distilled at atmospheric pressure from a steambath to remove the ether to give 57.1 g. of residue. A gas chromatogramof this crude residue showed the presence of8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl esterand of bis-(4-chlorophenyl)-disulfide.

In order to remove the by-product bis(4-chlorophenyl)disulfide, 30.9 g.of the above crude mixture was added to a 1 liter three-necked flaskprovided with a condenser and an inlet for nitrogen. A solution of 4.8g. of sodium hydroxide in 250 ml. of ethanol was added, and theresulting solution was refluxed for 1 hour under nitrogen. The ethanolwas removed in vacuo (steam bath, rotary evaporator) and 200 ml. ofwater added. The solution was acidified with dilute hydrochloric acid.After the precipitated 8-chloro-1,2,3,4-tetrahydrodibenzothiopheneacetic acid had settled, the supernatant liquid was decanted. 100 Ml. ofether was added to the wet semi-solid acid, and the mixture swirled. Theinsoluble 8-chloro-1,2,3,4-tetrahydrodibenzothiopheneacetic acid wasfiltered off, washed with 50 ml. of ether, and dried in a vacuum ovenovernight at 50°. The yield of8-chloro-1,2,3,4-tetrahydrodibenzothiophene acetic acid was 26 g.), mp195°-202°. Re-esterification was carried out by adding 25.4 g. of theabove acid to 400 ml. of ethanol saturated at room temperature withhydrogen chloride. After the solution was refluxed for 6 hours, theethanol was removed in vacuo (steam bath, rotary evaporator), and 300ml. of benzene was added to the residue. The benzene solution was firstextracted twice with 75 ml. of water and then twice with 75 ml. of 6%sodium bicarbonate. The benzene solution was dried over anhydrouspotassium carbonate and distilled in vacuo to remove the benzene. Theweight of the crude ester was 26.6 g., m.p. 55°-60°. Crystallizationfrom hexane gave 22.1 g. of pure8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester,m.p. 64°-66°.

EXAMPLE 7 Preparation of 8-chloro-dibenzothiophene-3-acetic acid ethylester

Into a 2 liter three-necked flask provided with a condenser, stirrer anddropping funnel was added 31.2 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml. of dioxane. To thesolution, heated to reflux, was added at a rapid rate a solution of 21.2g. of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethylester in 500 ml. of dioxane. The solution was refluxed and stirred for18 hours, cooled to room temperature, and filtered to remove the formedhydroquinone. The solvent was removed in vacuo (steam bath, rotaryevaporator), and the residue was dissolved in 300 ml. of methylenechloride. The solution was filtered, if necessary, and passed through acolumn containing about 200 g. of alumina (Woelm, grade I). The color ofthe solution was now a light yellow. The solvent was removed (steambath, rotary evaporator), and the weight of sticky solid was 18.6 g. Thelatter was recrystallized from hexane and yielded 14 g. of8-chloro-dibenzothiophene-3-acetic acid ethyl ester, mp 88°-90°.

EXAMPLE 8 Preparation of 8-chloro-dibenzothiophene-3-acetic acid

To a 500 ml. flask, fitted with a condenser and containing a solution of1.84 g. of sodium hydroxide in 150 ml. of ethanol was added 14 g. of8-chloro-dibenzothiophene-3-acetic acid ethyl ester. After the solutionwas refluxed for 1 hour, the solvent was removed in vacuo (steam bath,rotary evaporator), the residue dissolved in 100 ml. of water, and theaqueous solution acidified with dilute hydrochloric acid. The8-chloro-dibenzothiophene-3-acetic acid was removed by filtration,washed with water and dried at 60° C. in a vacuum oven overnight. Theyield of 8-chloro-dibenzothiophene-3-acetic acid, after crystallizationfrom i-propanol, was 8 g., mp 220°-221°.

EXAMPLE 9 Preparation of 3-(2-chlorophenylthio)-4-ketocyclohexane aceticacid ethyl ester

28 G. of 2-chlorothiophenol and a solution of 10.8 g. of 85% potassiumhydroxide in 300 ml. of ethanol were each placed in a 3 literthree-necked flask, provided with a condenser, nitrogen inlet, droppingfunnel and stirrer. The solution was brought to reflux and a solution of50.6 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml.of ethanol was added over a period of one hour to the refluxingsolution. After the addition, the solution was stirred at reflux for onehour, cooled to room temperature, and filtered to remove the potassiumbromide. After removal of the ethanol in vacuo (steam bath, rotovapor),300 ml. of water was added to the residue, the product was extractedthree times with 200 ml. of ether and the ether extract dried overanhydrous magnesium sulfate. After removal of ether from a steam bath atatmospheric pressure, the residue was distilled in vacuo. A forerun wascollected at 100°-190° (1 mm), while a main fraction was collected at190° -222° (1 mm). The yield of3-(2-chlorophenylthio)-4-ketocyclohexaneacetic acid ethyl ester from themain fraction was 33.9 g., b.p. 205°-215/0.7 mm.

EXAMPLE 10 Preparation of6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester

33.9 G. of the above distilled3-(2-chlorophenylthio)-4-ketocyclohexaneacetic acid ethyl ester added to600 g. of polyphosphoric acid, contained in a 2 liter, three-neckedflask, provided with a stirrer and condenser. The mixture was heated ona steam bath for 90 minutes and then poured into a mixture of 1 kilogramof ice and 1 liter of water. The mixture was stirred until the dark oilycomplex was decomposed and a light yellow color appeared. The productwas extracted twice with 500 ml. of ether. The ether extract was washedtwice with 100 ml. of water, then with 100 ml. of saturated sodiumbicarbonate solution, dried over anhydrous potassium carbonate, anddistilled at atmospheric pressure from a steam bath to remove the ether.The yield of 6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acidethyl ester was 8.5 g., b.p. 195°-210/0.7 mm, mp 51°-53° (pentane).

EXAMPLE 11 Preparation of 6-chloro-dibenzothiophene-3-acetic acid ethylester

Into a 2 liter three-necked flask provided with a condenser, stirrer anddropping funnel was added 6 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml. of dioxane. To thesolution, heated to reflux, was added at a rapid rate a solution of 3.3g. of 6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethylester in 50.0 ml. of dioxane. The solution was refluxed and stirred for18 hours, cooled to room temperature, and filtered to remove thehydroquinone. The solvent was removed in vacuo (steam bath, rotaryevaporator) and the residue was dissolved in 300 ml. of methylenechloride. The solution was filtered, if necessary, and passed through acolumn containing about 200 g. of alumina (Woelm, grade I). The solventwas removed (steam bath, rotary evaporator). The resulting solid wasrecrystallized from hexane and yielded 1.3 g. of6-chloro-dibenzothiophene-3-acetic acid ethyl ester, mp 62°-64°(hexane).

EXAMPLE 12 Preparation of 6-chloro-dibenzothiophene-3-acetic acid

To a 100 ml. flask, fitted with a condenser and containing a solution of0.24 g. of potassium hydroxide in 30 ml. of ethanol was added 1.3 g. of6-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solutionwas refluxed for 1 hour, the solvent was removed in vacuo (steam bath,rotary evaporator), the residue dissolved in 100 ml. of water, and theaqueous solution acidified with dilute hydrochloric acid. The6-chlorodibenzothiophene-3-acetic acid was removed by filtration, washedwith water and dried at 60° in a vacuum oven overnight. The yield of6-chlorodibenzothiophene-3-acetic acid, after crystallization fromacetonitrile was 0.8 g., mp 226°-228°.

EXAMPLE 13 Preparation of3-(4-i-butylphenylthio)-4-ketocyclohexaneacetic acid ethyl ester

31.4 G. of 4-i-butylthiophenol and a solution of 10.6 g. of 85%potassium hydroxide in 300 ml. of ethanol were each placed in a 3 literthree-necked flask, provided with a condenser, nitrogen inlet, droppingfunnel and stirrer. The solution was brought to reflux and a solution of49.5 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml.of ethanol was added over a period of one hour to the refluxingsolution. After the addition, the solution was stirred at reflux for onehour, cooled to room temperature, and filtered to remove the potassiumbromide. After removal of the ethanol in vacuo (steam bath, rotaryevaporator), 300 ml. of water was added to the residue, the product wasextracted three times with 200 ml. of ether and the ether extract driedover anhydrous magnesium sulfate. After removal of ether from a steambath at atmospheric pressure, the residue was distilled in vacuo. Ayield of 42.5 g. of 3-(4-i-butylphenylthio)-4-ketocyclohexane aceticacid ethyl ester was obtained, b.p. 205-220/2.0 mm.

EXAMPLE 14 Preparation of8-i-butyl-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester

42.5 G. of the above distilled 3-(4-i-butylphenylthio)-4-ketocyclohexaneacetic acid ethyl ester was added to 700 g. of polyphosphoric acid,contained in a 2 liter three-necked flask, provided with a stirrer andcondenser. The mixture was heated on a steam bath for 90 minutes andthen poured into a mixture of 1 kilogram of ice and 1 liter of water.The mixture was stirred until the dark oily complex was decomposed and alight yellow color appeared. The product was extracted twice with 500ml. of ether. The ether extract was washed twice with 100 ml. of water,then with 100 ml. of saturated sodium bicarbonate solution, dried overanhydrous potassium carbonate, and distilled at atmospheric pressurefrom a steam bath to remove the ether. The yield of8-i-butyl-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl esterwas 24.4 g., b.p. 195-205/0.7 mm.

EXAMPLE 15 Preparation of 8-i-butyldibenzothiophene-3-acetic acid ethylester

Into a 2 liter three-necked flask provided with a condenser, stirrer anddropping funnel was added 16.6 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 200 ml. of xylene. To thesolution, heated to reflux, was added at a rapid rate a solution of 10.7g. of 8-i-butyl-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethylester in 200 ml. of xylene. The solution was refluxed and stirred for 18hours, cooled to room temperature, and filtered to remove thehydroquinone. The solvent was removed in vacuo (steam bath, rotaryevaporator) and the residue was dissolved in 300 ml. of methylenechloride. The solution was filtered, if necessary, and passed through acolumn containing about 200 g. of alumina (Woelm, grade I). The solventwas removed (steam bath, rotary evaporator). The product wasrecrystallized from hexane and yielded 4.7 g. of8-i-butyldibenzothiophene-3-acetic acid ethyl ester, b.p. 200-215/0.7mm.

EXAMPLE 16 Preparation of 8-i-butyl-dibenzothiophene-3-acetic acid

To a 500 ml. flask, fitted with a condenser and containing a solution of0.81 g. of potassium hydroxide in 125 ml. of ethanol was added 4.7 g. of8-i-butyldibenzothiophene-3-acetic acid ethyl ester. After the solutionwas refluxed for 1 hour, the solvent was removed in vacuo (steam bath,rotary evaporator), the residue dissolved in 100 ml. of water, and theaqueous solution acidified with dilute hydrochloric acid. The productwas removed by filtration, washed with water and dried at 60° in avacuum oven overnight. The yield of 8-i-butyl-dibenzothiophene-3-aceticacid after crystallization from i-propanol was 1.5 g., mp 133°-135°(heptane).

EXAMPLE 17 Preparation of 9-chlorodibenzothiophene-3-acetic acid

(A) 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester.

In a 3-l. three-necked flask, provided with a condenser, nitrogen inlet,dropping funnel and stirrer were placed 23.8 g. of 3-chlorothiophenoland a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. ofethanol. The solution was brought to reflux, and a solution of 43 g. of3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 250 ml. of ethanolwas added over a period of one hour. After the addition, the solutionwas stirred at reflux for one hour, cooled to room temperature andfiltered to remove the potassium bromide. After removal of the ethanolin vacuo on the steam bath, 150 ml. of water was added to the residue,the product extracted three times with 100 ml. of ether, and the etherextract was dried over anhydrous magnesium sulfate. After removal of theether from a steam bath at atmospheric pressure, the residue wasdistilled in vacuo. The yield of3-(3-chlorophenylthio)-4-oxycyclohexaneacetic acid ethyl ester was 12.2g.; b.p. 195°-225°/2 mm.

(B) 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethylester.

To 200 g. of polyphosphoric acid contained in a 1-l. three-necked flask,provided with a stirrer and condenser was added 8.0 g. of3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester. Themixture was heated on a steam bath for 90 minutes and then poured into amixture of 200 g. of ice and 200 ml. of water with stirring, which wascontinued until the dark oily complex was decomposed and a light yellowcolor appeared. The product was extracted twice with 200 ml. of ether.The ether extract was washed twice with 50 ml. of water and then with 50ml. of saturated sodium bicarbonate solution. The solution was driedover anhydrous potassium carbonate and then filtered. The ether wasremoved on a steam bath in a rotary evaporator at atmospheric pressure,and the residue was distilled at reduced pressure. At 205°-220°/2 mm. ayield of 3.3 g. of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-aceticacid ethyl ester was obtained.

(C) 9-chlorodibenzothiophene-3-acetic acid ethyl ester.

To a 1-l. three-necked flask provided with a condenser, stirrer anddropping funnel was added 11 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 500 ml. of dioxane.To the solution heated to reflux, was added at a rapid rate a soluton of6 g. of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethylester in 100 ml. of dioxane. The solution was refluxed and stirred for24 hours, cooled to room temperature and then filtered to remove thehydroquinone. The solvent was removed in vacuo on the steam bath, andthe residue was dissolved in 200 ml. of methylene chloride. Thissolution was passed through a column containing about 150 g. of alumina(Woelm, grade 1). The solvent was removed on the steam bath and theresidue was crystallized from alcohol. The yield of9-chlorodibenzothiophene-3-acetic acid ethyl ester was 1.1 g., m.p.82°-84°.

(D) 9-chlorodibenzothiophene-3-acetic acid.

To a 100 ml. flask, fitted with a condenser and containing a solution of0.28 g. of potassium hydroxide in 50 ml. of ethanol was added 1.1 g. of9-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solutionwas refluxed for four hours, the solvent was removed in vacuo on thesteam bath, the residue was dissolved in 50 ml. of water, and theaqueous solution was acidified with dilute hydrochloric acid. Theproduct was filtered, washed with 20 ml. of water, and dried at 60° in avacuum over for 12 hours. The yield of 9-chlorodibenzothiophene-3-aceticacid, after crystallization from methanol, was 0.8 g. (m.p. 203°-206°).

EXAMPLE 18 Preparation of 8-methyldibenzothiophene-3-acetic acid

(A) 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester.

In a 2 l. three-necked flask provided with a condenser, nitrogen inlet,dropping funnel and stirrer were placed 73.5 g. of p-toluenethiol and asolution of 33 g. of 85% potassium hydroxide in 500 ml. of ethanol. Thesolution was brought to reflux, and a solution of 146.4 g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 500 ml. ofethanol was added over a period of one hour. After the addition, thesolution was stirred at reflux for one hour. After removal of theethanol in vacuo on the steam bath, 300 ml. of water was added, and theproduct was extracted three times with 200 ml. of ether. The ethersolution was dried over anhydrous magnesium sulfate, and then thesolvent was removed on the steam bath. The residue was crystallized fromheptane; yield 66 g. of3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester,m.p. 87°-89°.

(B) 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethylester.

To 130 g. of polyphosphoric acid contained in a 500 ml. three-neckedflask provided with a stirrer and condenser, was added 13 g. of3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester. Themixture was heated on a steam bath for 90 minutes and then poured onto amixture of 200 g. of ice and 200 ml. of water. The mixture was stirreduntil the dark oily complex was decomposed, and a light yellow colorappeared. The product was extracted with ether, and the solution thenwashed with water until it was neutral. After drying over anhydrouspotassium carbonate, the ether was distilled off on the steam bath, andthe residue was crystallized from methanol. The yield of8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethylester, m.p. 68°-69°, was 6 g.

(C) 8-methyldibenzothiophene-3-carboxylic acid ethyl ester.

To a 500 ml. three-necked flask provided with a condenser, stirrer anddropping funnel was added 10 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 200 ml. of dioxane.To the solution, heated to reflux, was added at a rapid rate a solutionof 5.5 g. of 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylicacid ethyl ester in 50 ml. of dioxane. The solution was refluxed andstirred for 20 hours, cooled to room temperature and filtered to removethe hydroquinone. The solvent was removed in vacuo on the steam bath,and the residue was dissolved in 100 ml. of methylene chloride. Thesolution was passed through a column containing about 75 g. of alumina(Woelm, grade I). The solvent was removed, and the residue wascrystallized from methanol. The yield of8-methyldibenzothiophene-3-carboxylic acid ethyl ester was 4.2 g., m.p.83°-87°.

(D) 8-methyldibenzothiophene-3-carboxylic acid.

To a solution of 0.73 g. of potassium hydroxide in 50 ml. of ethanol wasadded 3.5 g. of 8-methyldibenzothiophene-3-carboxylic acid ethyl ester.The solution was refluxed for 3 hours. The solvent was removed in vacuoon the steam bath, and the crude potassium salt was dissolved in 50 ml.of water. The solution was acidified with dilute hydrochloric acid andthe product was filtered off and dried. The yield of8-methyldibenzothiophene-3-carboxylic acid was 2 g., m.p. 290°-291°.

(E) 3-chlorocarbonyl-8-methyldibenzothiophene.

A solution of 3 g. of oxalyl chloride in 50 ml. of benzene was addeddropwise with stirring to a suspension of 3.5 g. of the crude potassiumsalt of 8-methyldibenzothiophene-3-carboxylic acid in 100 ml. ofbenzene. The mixture was filtered and the solvent removed in vacuo onthe steam bath. The residue, after crystallization from hexane, yielded2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene, m.p. 127°-128°.

(F) 3-diazomethylcarbonyl-8-methyldibenzothiophene.

A solution of 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene in 75ml. of ether was added dropwise to a solution of 0.81 g. of diazomethanein 100 ml. of ether in an ice bath. The solution was stirred overnight,and the ether was removed on the steam bath. The crude product (2.5 g.),3-diazomethylcarbonyl-8-methyldibenzothiophene, was used directly in thenext step.

(G) 8-methyldibenzothiophene-3-acetic acid ethyl ester.

To a refluxing solution of 2.5 g. of crude3-diazomethylcarbonyl-8-methyldibenzothiophene in 50 ml. of alcohol wasadded dropwise, with stirring, a solution of 1.0 g. of silver benzoatein 10 ml. of triethylamine. The solution was refluxed until evolution ofnitrogen had ceased. The solution was filtered, and the solvent wasremoved in vacuo on the steam bath. The residue was crystallized frompetroleum ether (30°-60°) to yield 1.3 g. of8-methyldibenzothiophene-3-acetic acid ethyl ester, m.p. 45°-48°.

(H) 8-methyldibenzothiophene-3-acetic acid.

To a solution of 0.27 g. of potassium hydroxide in 50 ml. of alcohol,was added 1.3 g. of 8-methyldibenzothiophene-3-acetic acid ethyl ester,and the solution was refluxed for 3 hours. The solvent was removed invacuo, and the residue was dissolved in 50 ml. of water. The solutionwas acidified with dilute hydrochloric acid and the product was filteredoff and dried. Recrystallization from acetonitrile yielded 0.5 g. of8-methyldibenzothiophene-3-acetic acid, m.p. 185°-187°.

EXAMPLE 19 Preparation of dibenzothiophene-3-acetic acid

(A) 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester.

To a 1 l. three-necked flask provided with a stirrer, condenser anddropping funnel and containing a solution of 25.5 g. of4-ketocyclohexanecarboxylic acid ethyl ester in 450 ml. of anhydrousether cooled to -10° was added dropwise over 45 minutes 24 g. ofbromine. The resulting colorless solution was washed with 3×100 ml. ofwater, then with 2×50 ml. of 5% sodium bicarbonate solution and finallywith 2×100 ml. of water. The ether solution was dried over anhydrousmagnesium sulfate and then the solvent was removed on a steam bath. Theyield of crude 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester was37 g.

(B) 3-phenylthio-4-ketocyclohexanecarboxylic acid ethyl ester.

In a 2 l. three-necked flask provided with a condenser, nitrogen inlet,dropping funnel and stirrer, were placed 16.5 g. of benzenethiol and asolution of 10 g. of potassium hydroxide in 400 ml. of alcohol. Thesolution was brought to reflux and a solution of 37 g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 200 ml. ofalcohol was added over a period of 1 hour. The reaction mixture was thenstirred and refluxed for 1 hour. The solvent was removed on a steam bathat reduced pressure and 200 ml. of water added to the residue. The oilwas extracted with ether and the solution dried over anhydrous potassiumcarbonate. The ether was removed on a steam bath and the residue, onvacuum distillation, yielded 20 g. of3-phenylthio-4-ketocyclohexanecarboxylic acid ethyl ester, b.p.198°-210° at 2 mm.

(C) 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester.

A mixture of 10 g. of 3-phenylthio-4-ketocyclohexane carboxylic acidethyl ester and 130 g. of polyphosphoric acid was stirred on a steambath for 1.5 hours. It was then poured onto a mixture of 400 g. of iceand 400 ml. of water. The oil was extracted with 2×100 ml. of ether andthe ether extract washed with 2×50 ml. of water and then with 50 ml. of5% sodium bicarbonate solution. The ether solution was dried overanhydrous potassium carbonate, and the solvent then removed on a steambath. The crude product was distilled at reduced pressure and yielded 5g. of 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester,b.p. 190°-195° at 2 mm.

(D) Dibenzothiophene-3-carboxylic acid ethyl ester.

To a solution of 2.5 g. of1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester in 100ml. of dioxane was added 4.7 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The solution was stirred andrefluxed for 31 hours. The solution was cooled and the hydroquinonefiltered off. The dioxane was removed on a steam bath under reducedpressure. The residue was dissolved in 100 ml. of methylene chloride andthe solution passed through a column containing about 75 g. of alumina(Woelm, grade 1). The solvent was removed on a steam bath and theresidue crystallized from hexane. The yield ofdibenzothiophene-3-carboxylic acid ethyl ester, m.p. 74°-78° was 1.7 g.

(E) Dibenzothiophene-3-carboxylic acid potassium salt.

To 200 ml. of alcohol containing 2.7 g. of potassium hydroxide was added13.2 g. of dibenzothiophene-3-carboxylic acid ethyl ester and thesolution was refluxed, stirred for 4 hours and filtered. The insolubledibenzothiophene-3-carboxylic acid potassium salt was filtered off andweighed, after drying at 80° in a vacuum oven, 8.9 g. Thedibenzothiophene-3-carboxylic acid, which can be obtained from the abovepotassium salt is a known compound [H. Gilman, A. L. Jacoby and H. A.Pacevitz, J. Org. Chem. 3, 120 (1938)].

(F) 3-chlorocarbonyldibenzothiophene.

To a suspension of 8.9 g. of dibenzothiophene-3-carboxylic acidpotassium salt in 200 ml. of benzene was added dropwise with stirringover a period of 30 minutes, a solution of 6.4 g. of oxalyl chloride in50 ml. of benzene. The mixture was stirred and refluxed for two hours.The mixture was filtered and the solvent was removed in vacuo on thesteam bath. The residue, 3-chlorocarbonyldibenzothiophene (7.9 g.) wasused directly in the next step.

(G) 3-diazomethylcarbonyldibenzothiophene.

A solution of 7.9 g. of crude 3-chlorocarbonyldibenzothiophene in 700ml. of ether was added with stirring to a solution of 2.7 g. ofdiazomethane in 180 ml. of ether in an ice bath. The solution wasstirred for 7 hours and then the solvent was removed, on a steam bath,to yield the crude 3-diazomethylcarbonyldibenzothiophene (7.5 g.) whichwas used directly in the next step.

(H) Dibenzothiophene-3-acetic acid ethyl ester.

To a refluxing solution of 7.5 g. of crude3-diazomethylcarbonyldibenzothiophene in 100 ml. of alcohol was added,dropwise with stirring, a solution of 1 g. of silver benzoate in 10 ml.of triethylamine. The solution was then refluxed for one hour, filtered,and the solvent was removed in vacuo. The residue, after crystallizationfrom petroleum ether (30°-60°) yielded 2.7 g. ofdibenzothiophene-3-acetic acid ethyl ester, m.p. 60°-62°.

(I) Dibenzothiophene-3-acetic acid.

To a solution of 0.56 g. of potassium hydroxide in 75 ml. of ethanol wasadded 2.7 g. of dibenzothiophene-3-acetic acid ethyl ester. The solutionwas refluxed 3 hours and the solvent then removed in vacuo. The residuewas dissolved in 50 ml. of water, and the solution was acidified withdilute hydrochloric acid. The solid was filtered off and dried in vacuoat 50°. Recrystallization from acetonitrile yielded 1 g. ofdibenzothiophene-3-acetic acid, m.p. 174°-176°.

EXAMPLE 20 Preparation of 7-chlorodibenzothiophene-3-acetic acid

(A) Dibenzothiophene-3-carboxylic acid ethyl ester 5-oxide.

8.3 G. of chlorine was bubbled into a solution of 23.8 g. ofdibenzothiophene-3-carboxylic acid ethyl ester in 600 ml. of carbontetrachloride cooled to 5°. The solution was poured onto ice, and themixture was well shaken. The solid was filtered off, dried in vacuum at50° and then crystallized from acetonitrile to yield 11.6 g. ofdibenzothiophene-3-carboxylic acid ethyl ester 5-oxide, m.p. 210°-213°.

(B) 7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide.

To 250 ml. of 90% nitric acid kept at 22°-25°, 25 g. ofdibenzothiophene-3-carboxylic acid ethyl ester 5-oxide was added, inportions. The solution was stirred for 15 minutes and then poured ontoice. The solid was filtered off, washed with water until neutral anddried in a vacuum oven at 50°. The solid was crystallized from1,2-dichloroethane to yield 24.7 g. of7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide, m.p.245°-250°.

(C) 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride.

A mixture of 21.9 g. of 7-nitrodibenzothiophene-3-carboxylic acid ethylester 5-oxide, 250 ml. of acetic acid, and 1.7 g. of 10% palladium oncarbon was shaken at an initial pressure of 50 pounds of hydrogen andheated to 60°. After one hour the uptake of hydrogen had ceased. Themixture was removed from the hydrogenation apparatus, cooled to roomtemperature and filtered. After removal of the solvent in vacuo on thesteam bath, the residue was dissolved in 300 ml. of ethyl acetate, andthe product was precipitated as the hydrochloride by bubbling inhydrogen chloride. The yield of 7-aminodibenzothiophene-3-carboxylicacid ethyl ester hydrochloride was 17.1 g. (m.p. 260°-265°). A smallportion, after crystallization from methanol, melted at 270°-275°.

(D) 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester.

A solution of 28.7 g. of 7-aminodibenzothiophene-3-carboxylic acid ethylester hydrochloride in 300 ml. of acetic acid was added at 15° tonitrosylsulfuric acid prepared from 19.4 g. of sodium nitrite and 100ml. of concentrated sulfuric acid. The mixture was stirred for 15minutes and then 1 l. of ether was added to precipitate the diazoniumsulfate. The mixture of the diazonium sulfate and sodium sulfate wasfiltered off, washed with ether, and air-dried. The mixture was thenadded, in portions at 5° to a cuprous chloride solution prepared from9.4 g. of cuprous chloride, 375 ml. of water and 280 ml. of conc.hydrochloric acid. After the addition, the contents were heated on asteam bath until nitrogen evolution ceased. The solid was filtered off,washed with water and then dried in a vacuum oven. The solid, aftercrystallization from hexane, yielded 18 g. of7-chlorodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 120°-122°.

(E) 7-chlorodibenzothiophene-3-carboxylic acid potassium salt.

A solution of 4.1 g. of potassium hydroxide (85%) in 100 ml. of alcoholwas added to a solution of 18.1 g. of7-chlorodibenzothiophene-3-carboxylic acid ethyl ester in 450 ml. ofwarm ethanol. The combined solutions were stirred and refluxed for 8hours. After cooling to room temperature, the mixture was filtered togive 16.5 g. of the potassium salt.

(F) 3-chlorocarbonyl-7-chlorodibenzothiophene.

A solution of 10.5 g. of oxalyl chloride in 100 ml. of benzene wasadded, with stirring, to a suspension of 16.53 g. of7-chlorodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. ofbenzene. The mixture was stirred and refluxed for two hours and thenfiltered. On distillation to dryness on the steam bath in vacuo 9 g. ofcrude 3-chlorocarbonyl-7-chlorodibenzothiophene was obtained as aresidue.

(G) 7-chlorodibenzothiophene-3-acetic acid ethyl ester.

A solution of 9 g. of 3-chlorocarbonyl-7-chlorodibenzothiophene in 100ml. of dioxane was added dropwise to a solution of 5.3 g. ofdiazomethane in 250 ml. of ether with cooling in an ice bath. Thesolution was stirred overnight, and the solvent was then removed bydistillation in vacuo. The residue was dissolved in 600 ml. of alcohol,and to the refluxing solution was added dropwise over one hour asolution of 1 g. of silver benzoate in 100 ml. of triethylamine. Thesolution was refluxed for one hour after the addition and then filtered.The solvent was removed by distillation in vacuo from a steam bath andthe residue was crystallized from hexane, yield, 4.8 g. of7-chlorodibenzothiophene-3-acetic acid ethyl ester, m.p. 68°-70°.

(H) 7-chlorodibenzothiophene-3-acetic acid.

To a solution of 1 g. of potassium hydroxide in 75 ml. of alcohol wasadded 4.8 g. of 7-chlorodibenzothiophene-3-acetic acid ethyl ester.After refluxing for 3 hours, the solvent was removed in vacuo on thesteam bath, and 50 ml. of water was added to dissolve the residue. Theaqueous solution was acidified with hydrochloric acid, and the productfiltered off. The solid was crystallized from acetonitrile to yield 1.7g. of 7-chlorodibenzothiophene-3-acetic acid, m.p. 198°-200°.

EXAMPLE 21 Preparation of 7-dimethylaminodibenzothiophene-3-acetic acidethyl ester

(A) 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride

A mixture of 24 g. of 7-nitrodibenzothiophene-3-carboxylic acid ethylester 5-oxide, 200 ml. of acetic acid and 2.4 g. of 10% palladium carbonwas hydrogenated at 50° at an initial pressure of 50 lbs. Aftercompletion of the hydrogenation in 3 hours, the mixture was filtered,and the acetic acid was removed in vacuo (steam bath, rotaryevaporator). The residue was dissolved in 250 ml. of ethyl acetate, andhydrogen chloride was bubbled into the solution. The precipitatedhydrochloride of 7-aminodibenzothiophene-3-carboxylic acid ethyl esterweighed 20 g.; mp 270°-275°.

(B) 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester

A mixture of 7.3 g. of 7-aminodibenzothiophene-3-carboxylic acid ethylester hydrochloride and 5.0 g. of trimethyl phosphate were heated at160° for 45 minutes. After cooling to room temperature, 75 ml. of ethylacetate was added, and the solution was extracted with 25 ml. of water.The ethyl acetate was removed in vacuo (steam bath, rotary evaporator),and the residue was crystallized from ethanol. The yield of7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester was 2.8g.; mp 160°-162°.

(C) 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt

To a solution of 0.5 g. of potassium hydroxide in 100 ml. of ethanol wasadded 2.8 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid ethylester. The solution was stirred and refluxed for 3 hours during whichtime the potassium salt precipitated. The salt was filtered off, washedwith ether and air dried. The yield of7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt was 1.9g.

(D) 7-dimethylaminodibenzothiophene-3-carbonyl chloride

To a suspension of 1.9 g. of7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt in 100ml. of refluxing benzene was added over a period of 20 minutes asolution of 1.2 g. of oxalyl chloride in 25 ml. of benzene. The solutionwas then stirred and refluxed for 3 hours. The hot solution wasfiltered, and the filtrate was distilled to dryness in vacuo (steambath, rotary evaporator). The residue of crude7-dimethylaminodibenzothiophene-3-carbonyl chloride weighed 1.8 g.

(E) 7-dimethylaminodibenzothiophene-3-acetic acid ethyl ester

To a 250 ml. 3-necked flask provided with a stirrer, dropping funnel andcondenser was added a solution of 0.7 g. of diazomethane in 50 ml. ofether. The flask was cooled in an ice bath, and a solution of 1.8 g. of7-dimethylaminodibenzothiophene-3-carbonyl chloride in 50 ml. ofanhydrous ether and 50 ml. of tetrahydrofuran was added dropwise over aperiod of 15 minutes. The ice bath was removed and the solution stirredfor 2.5 hours. After removal of the solvent by distillation in vacuo onthe steam bath, the residue was crystallized from toluene. The yield of3-diazomethylcarbonyl-7-dimethylaminodibenzothiophene was 0.3 g; mp173°-175°. To a refluxing solution of the diazo compound (0.3 g.) in 50ml. of alcohol was added dropwise, over 1 hour with stirring, a solutionof 1 g. of silver benzoate in 10 ml. of triethylamine. The solution wasfiltered and the solvents removed from a steam bath in vacuo. Theresidue was crystallized from methanol and yielded 50 mg. of7-dimethylaminodibenzothiophene-3-acetic acid ethyl ester; mp 115°-120°.

EXAMPLE 22 Preparation of 8-chlorodibenzothiophene-3-acetamide

A solution of 2.76 g. of 8-chlorodibenzothiophene-3-acetic acid in 10ml. of thionyl chloride was stirred for 1 hour and then distilled atreduced pressure at room temperature. The residue of crude8-chlorodibenzothiophene-3-acetyl chloride, m.p. 92°-99°, was thendissolved in 100 ml. of benzene, and the solution was saturated withammonia. The amide was filtered off, washed with water and crystallizedfrom acetic acid. The product, 8-chlorodibenzothiophene-3-acetamideweighed 2 g. and melted at 237°-238°.

EXAMPLE 23 Preparation of 8-chlorodibenzothiophene-3-ethanol

3.05 G. of 8-chlorodibenzothiophene-3-acetic acid ethyl ester was addedto 0.45 g. of lithium aluminum hydride in 100 ml. of ether. The solutionwas refluxed for one hour and then treated with 2 ml. of water. Thesolution was filtered and the ether removed from a steam bath. Theresidue was crystallized from acetonitrile and yielded 1.1 g. of8-chlorodibenzothiophene-3-ethanol, m.p. 98°-100°.

EXAMPLE 24 Preparation of 8-chlorodibenzothiophene-3-acetic acid,2-dimethylaminoethyl ester hydrochloride

A mixture of 2.76 g. of 8-chlorodibenzothiophene-3-acetic acid, 3.04 g.of potassium carbonate, 1.73 g. of dimethylaminoethyl chloridehydrochloride, and 250 ml. of dimethylformamide was stirred and heatedat 120° for 4 hours. The solvent was removed in vacuo on the steam bath,and 75 ml. of water added to the residue. The oil was extracted withethyl acetate and the crude product precipitated as the hydrochloride bythe addition of hydrogen chloride. On crystallization from acetone, 1.5g. of 8-chlorodibenzothiophene-3-acetic acid 2-dimethylaminoethyl esterhydrochloride, m.p. 179°-181°, was obtained.

EXAMPLE 25

    ______________________________________                                        Tablet Formulation                                                                                   Per Tablet                                             ______________________________________                                        Racemic 8-chloro-dibenzothiophene-                                            3-acetic acid            25 mg.                                               Dicalcium Phosphate Dihydrate, unmilled                                                                175 mg.                                              Corn Starch              24 mg.                                               Magnesium Stearate       1 mg.                                                Total Weight             225 mg.                                              ______________________________________                                    

Procedure:

1. 25 Parts of racemic 8-chloro-dibenzothiophene-3-acetic acid and 24parts of corn starch are mixed together and passed through a No. 00screen in Model "J" Fitzmill with hammers forward.

2. This premix is then mixed with 175 parts of dicalcium phosphate andonehalf of a part of the magnesium stearate, and passed through a No. 1Ascreen in Model "J" Fitzmill with knives forward, and slugged.

3. The slugs are passed through a No. 2A plate in a Model "D" Fitzmillat slow speed with knives forward, and the other one-half of a partmagnesium stearate is added.

4. The mixture is mixed and compressed into tablets weighing 225 mg.

EXAMPLE 26

    ______________________________________                                        Capsule Formulation                                                                                 Per Capsule                                             ______________________________________                                        Racemic 8-chloro-dibenzothiophene-3-                                          acetic acid             50 mg.                                                Lactose, U.S.P.         125 mg.                                               Corn Starch, U.S.P.     30 mg.                                                Talc, U.S.P.            5 mg.                                                 Total Weight            210 mg.                                               ______________________________________                                    

Procedure:

1. 50 Parts of racemic 8-chloro-dibenzothiophene-3-acetic acid is mixedwith 125 parts of lactose and 30 parts of corn starch in a suitablemixer.

2. The mixture is further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder is returned to the mixer, 5 parts talc are addedand blended thoroughly.

4. The mixture is filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine.

EXAMPLE 27

    ______________________________________                                        Tablet Formulation                                                                                  Per Tablet                                              ______________________________________                                        Racemic 8-chloro-dibenzothiophene-3-                                          acetic acid             100 mg.                                               Lactose, U.S.P.         202 mg.                                               Corn Starch, U.S.P.     80 mg.                                                Amijel BO11.sup.1       20 mg.                                                Calcium Stearate        8 mg.                                                 Total Weight            410 mg.                                               ______________________________________                                    

Procedure:

1. 100 Parts of racemic 8-chloro-dibenzothiophene-3-acetic acid, 202parts of lactose, 80 parts of corn starch and 20 parts Amijel BO11 areblended in a suitable mixer.

2. The mixture is granulated to a heavy paste with water and the moistmass is passed through a No. 12 screen. It is then dried overnight at110° F.

3. The dried granules are passed through a No. 16 screen and transferredto a suitable mixer. The calcium stearate is added and mixed untiluniform.

4. The mixture is compressed at a tablet weight of 410 mg. using tabletpunches having a diameter of approximately 5/8". (Tablets may be eitherflat or biconvex and may be scored if desired.)

EXAMPLE 28

    ______________________________________                                        Suppository Formulation                                                                             Per 1.3 Gm.                                                                   Suppository                                             ______________________________________                                        Racemic 8-chloro-dibenzothiophene-3-                                          acetic acid             0.025 mg.                                             Hydrogenated coconut oil                                                                              1.230 mg.                                             Carnauba Wax            0.045 gm.                                             ______________________________________                                    

Procedure:

1. 123 Parts of hydrogenated coconut oil and 4.5 parts of carnauba waxare melted in a suitable size glass-lined container (stainless steel mayalso be used), mixed well and cooled to 45° C.

2. 2.5 Parts of racemic 8-chloro-dibenzothiophene-3-acetic acid, whichhas been reduced to a fine powder with no lumps, is added and stirreduntil completely and uniformly dispersed.

3. The mixture is poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

4. The suppositories are cooled and removed from molds, and individuallywrapped in wax paper for packaging. (Foil may also be used.)

We claim:
 1. A compound of the formula ##STR15## wherein R'₁ is halogen,lower alkyl or lower alkoxy, and X and Y, independently, are hydrogen orlower alkyl, or, when X and Y are different, enantiomers.
 2. A compoundin accordance with claim 1, racemic2-(8-chloro-3-dibenzothienyl)propanol.
 3. A compound in accordance withclaim 2, 2-(8-chloro-3-dibenzothienyl)ethanol.